(Applicant?s abstract) Homozygous sickle cell disease (HbSS), known also as sickle cell anemia, results from inheritance of the sickle cell Betas-globin gene from both parents and is characterized usually by marked clinical severity. Many children with HbSS have delayed growth and sexual development. The reason for the delayed growth and associated poor weight gain is not well understood but it might be associated with the increased requirement for energy. The underlying physiological mechanism of this increase could be in part explained by the accelerated synthesis of new red blood cells (RBCs) and the altered catabolism of irreversibly sickled RBCs. However, how these metabolic events develop and progress during the accelerated growth occurring in HbSS adolescents is unknown. The central hypothesis of this application is that increased whole-body protein turnover and increased cardiac output, resulting in increased energy expenditure for basal needs and physical activity, divert energy and protein from normal growth pathways in HbSS adolescents. The rationale for the proposed research is that quantifying energy and protein needs ad finding the underlying mechanism(s) for stunting will lead us to establishing nutritional recommendations and designing specific supplementation for HbSS children and adolescents. The specific aims are: 1) to determine how much energy and protein is needed for optimal growth in adolescents with HbSS; 2) to explain how growth rate in HbSS adolescents is altered by increased demands for energy caused by higher whole-body protein turnover, and increased cardiac output; and 3) to quantify how much energy and protein is required for daily physical activity in adolescents with HbSS. In the proposed longitudinal study of HbSS adolescents, energy and protein balance will be measured in a controlled environment and assessed in free living. At regular intervals, all components of energy expenditure and the total 24-h energy balance will be measured continuously inside a whole-room indirect calorimeter while using stable isotopes techniques for assessing protein kinetics. Healthy (HbAA) adolescents matched initially for Tanner stage of sexual development, gender, and race will serve as controls in all experiments. The proposed research is significant, because it is expected to result in new guidelines for nutritional management of adolescents with HbSS that will significantly improve their growth rate and attendant weight gains. In addition, what is learned from this research will contribute to broader understanding of how HbSS affects energy and protein metabolism, how these changes alter growth in HbSS adolescents, and what underlying physiological mechanism(s) are involved.